Pharmacokinetic/Pharmacodynamic Modeling of Luteinizing Hormone (LH) Suppression and LH Surge Delay by Cetrorelix after Single and Multiple Doses in Healthy Premenopausal Women

Cetrorelix (CET) is a potent luteinizing hormone—releasing hormone (LH‐RH) antagonist and is used to prevent premature ovulation in IVF (in vitro fertilization) procedures. The objective of the present study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the LH suppression and LH surge delay after single doses (SD) and multiple doses (MD) of CET in healthy premenopausal women without ovarian stimulation. CET was given by subcutaneous route (SD, 0.25, 0.5, or 1 mg) on cycle day 3 and as similar multiple once‐a‐day doses from cycle day 3 to day 16 in two consecutive menstrual cycles. The concentration‐time data of CET and LH were used for PK/PD modeling. A two‐compartment model described the PK of CET with median terminal half‐life estimates of 9.2 and 54.5 hours after SD and MD, respectively. An indirect‐response Emax model was used to describe the LH suppression and the LH surge delay. LH suppression was linked to plasma concentrations of CET, while the delay in the LH surge was linked to the PK of CET through a hypothetical effect compartment. Since the SD regimen on day 3 did not cause significant delay, these values were used as controls in the analysis of surge delay in MD data. The IC50 (for suppression) estimate was 0.73 ng/ml for SD, and EC50 (surge delay) was 1.42 ng/ml for MD. The PK/PD model adequately described the LH suppression and the surge delay.

[1]  R. Frydman,et al.  Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). , 2000, Fertility and sterility.

[2]  D. Klingmüller,et al.  Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist Cetrorelix during ovarian stimulation. , 1994, Human reproduction.

[3]  J. Veldhuis,et al.  Reanalysis of the rat proestrous LH surge by deconvolution analysis. , 1993, The American journal of physiology.

[4]  D. Klingmüller,et al.  Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women. , 1994, European journal of endocrinology.

[5]  H. Tournaye,et al.  Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles. , 1999, Human reproduction.

[6]  A. Schueler,et al.  Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women. , 2001, Fertility and sterility.

[7]  B. Szende,et al.  Development of radioimmunoassay for a potent luteinizing hormone-releasing hormone antagonist. Evaluation of serum levels after injection of [Ac-3-(2-naphthyl)-D-Ala1, D-Phe(pCl)2, 3-(3-pyridyl)-D-Ala3, D-Cit6, D-Ala10] LHRH. , 1990, Arzneimittel-Forschung.

[8]  ASTA-Medica Ag.  Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist Cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study , 2000 .

[9]  Varun Garg,et al.  Comparison of four basic models of indirect pharmacodynamic responses , 1993, Journal of Pharmacokinetics and Biopharmaceutics.

[10]  K. Diedrich,et al.  Hormone profiles under ovarian stimulation with human menopausal gonadotropin (hMG) and concomitant administration of the gonadotropin releasing hormone (GnRH)-antagonist Cetrorelix at different dosages , 1996, Journal of Assisted Reproduction and Genetics.

[11]  R. Frydman,et al.  A single injection of a gonadotropin-releasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surge: further evidence for the role of GnRH during the LH surge. , 1994, Fertility and sterility.

[12]  T. Soboleva,et al.  A model of follicular development and ovulation in sheep and cattle. , 2000, Animal reproduction science.

[13]  William Francis Ganong,et al.  Review of Medical Physiology , 1969 .

[14]  Contemporary aspects of discrete peak-detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. , 1988, Endocrine reviews.

[15]  G. De Nicolao,et al.  Evaluation of pulse-detection algorithms by computer simulation of hormone secretion. , 1988, The American journal of physiology.

[16]  M L Johnson,et al.  Contemporary aspects of discrete peak-detection algorithms. II. The paradigm of the luteinizing hormone pulse signal in women. , 1992, Endocrine reviews.

[17]  M. Grigat,et al.  Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study. , 2000, Human reproduction.

[18]  S. Moenter,et al.  Gonadotropin-releasing hormone requirements for ovulation. , 1997, Biology of reproduction.

[19]  R. Hermann,et al.  Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers. , 1998, Human reproduction.

[20]  H. Derendorf,et al.  Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH‐RH antagonist, after subcutaneous administration in healthy premenopausal women , 2000, Clinical pharmacology and therapeutics.

[21]  M L Johnson,et al.  The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M L Johnson,et al.  A novel general biophysical model for simulating episodic endocrine gland signaling. , 1988, The American journal of physiology.